Multifunctional PEG Hydrogel Nano/Microparticles for Targeted Treatment of NSCLC

描述（由申请人提供）：拟议研究项目的长期目标是开发一种静脉（IV）给药的肺靶向纳米颗粒(NP)/凝胶微粒（GMP）递送系统，用于治疗非小细胞肺癌（NSCLC）。在初步诊断后，超过一半的局限性肺癌患者至少存活了5年，这表明限制原发性肺癌转移扩散的方法是有益的。虽然靶向治疗是提高药物浓度和减少副作用的有效方法，但肺靶向治疗的选择范围很窄。因此，迫切需要靶向肺给药方法来治疗非小细胞肺癌。提出了两个层次的目标。第一种是被动定位。静脉给药后，gmp选择性地在肺部积聚。我们令人信服的初步数据表明，被动靶向可以使抗癌药物效力提高10倍，并使全身药物浓度峰值降低10倍。二是主动定位。提出了两种类型的NPs来实现主动靶向。利用一种新的制造工艺，实现了高药物负载到NPs中，克服了疏水抗癌药物的溶解度限制。NP表面被选择性靶向癌细胞的配体功能化。第二种NP基团也与细胞表面配体功能化，然而，这些NP不是选择性地在癌细胞内递送药物，而是被设计成与癌细胞表面受体紧密结合并留在那里，以抑制转移信号级联。一旦GMP被动地在肺中积累，嵌入GMP的NPs就会扩散出去寻找癌细胞，从而产生高度的靶向特异性。提出了三个具体目标：目标1：设计和评估一系列gmp，以实现(a)在正常小鼠和正交异性肺癌小鼠模型中实现最佳的被动肺靶向效率、保留和消除；(b)最小的肺毒性（结构和功能改变和炎症）。目标2：设计、制造和评估能增强喜树碱（CPT）促凋亡作用的NPs和gmp。积极靶向NPs将被开发出来，特异性地将CPT和α硫辛酸（ALA）递送到肺癌细胞，以利用这两种化疗药物诱导的肿瘤细胞凋亡的协同作用。目的3：设计、制造和评估减少转移发生的cxcr4 /7靶向NPs和gmp。将研究两种主动靶向方法：(1)直接结合CXCR4/7受体；(2)抑制下游促转移信号因子NF-kB、ERK和/或MMP-9。如果成功，将生产一种可注射的肺部靶向给药系统，该系统：(1)利用被动靶向利用肺部的自然流动-过滤模式来实现高的局部和最小的全身药物浓度；(2)利用化疗诱导的肿瘤细胞凋亡和主动靶向的协同作用，减少所需的有效药物和MP剂量；(3)利用主动靶向，通过干扰CXCR4/7 - CXCL12趋化因子通路，减少转移灶的发生。

DESCRIPTION (provided by applicant): The long-term goal of the proposed research program is to develop an intravenously (IV) administered lung- targeted nanoparticle (NP)/gel microparticle (GMP) delivery system for the treatment of non-small cell lung cancer (NSCLC). After the initial diagnosis, greater than half of the patients with localized lung cancer survive at least 5 years suggesting a benefit to an approach that limits metastatic spread from the primary lung cancer. While targeting is an effective approach for improving drug concentrations and minimizing side effects, the options for lung targeting are narrow. Thus, targeted lung delivery approaches for treating NSCLC are urgently needed. Two levels of targeting are proposed. The first is passive targeting. GMPs selectively accumulate in the lung after IV administration. Our compelling preliminary data demonstrates that passive targeting achieves a 10-fold increase in anti-cancer drug potency and 10-fold lower peak systemic drug concentrations. The second is active targeting. Two types of NPs are proposed to achieve active targeting. Using a novel fabrication process, high drug loading into NPs is achieved that overcomes the solubility limitations of hydrophobic cancer drugs. The NP surfaces are functionalized with ligands that selectively target cancer cells. The second NP group is also functionalized with cell surface ligands, however, instead of delivering drug cargo selectively inside the cancer cell, these NPs are engineered to tightly bind to cancer cell surface receptors and remain there in order to inhibit the metastatic signaling cascade. Once the GMPs passively accumulate in the lung, the NPs imbedded in the GMP diffuse out and seek cancer cells resulting in an extraordinary degree of targeting specificity. Three specific aims are proposed: AIM 1: Engineer and evaluate a series of GMPs to achieve (a) optimal passive lung targeting efficiency, retention and elimination and (b) minimal pulmonary toxicity (structural and functional alterations and inflammation) in normal mice and in an orthotropic mouse model of lung cancer. AIM 2: Design, fabricate, and assess NPs and GMPs that enhance the pro-apoptotic effect of camptothecin (CPT). Actively targeted NPs will be developed that specifically deliver CPT and alpha lipoic acid (ALA) to lung cancer cells to exploit synergy in tumor cell apoptosis induced by these two chemotherapeutic agents. AIM 3: Design, fabricate, and assess CXCR4/7-targeted NPs and GMPs that reduce the occurrence of metastasis. Two active targeting approaches will be investigated: (1) direct CXCR4/7 receptor binding and (2) inhibition of downstream pro-metastatic signaling factors NF-kB, ERK and/or MMP-9. If successful, an injectable lung targeted drug delivery system will be produced that: (1) utilizes passive targeting to exploit the natural flow-filtration pattern of the lung to achieve high local and minimal systemic drug concentrations; (2) exploits synergy in chemotherapy-induced tumor cell apoptosis and active targeting to reduce the required effective drug and MP doses; and (3) utilizes active targeting to reduce the occurrence of metastatic lesions by interfering with the CXCR4/7 - CXCL12 chemokine pathway.